Christopher K. Zarins, M.D. - US grants

Intimal thickening is a feature of the normal healing response at graft anastomoses. Yet, in grafts to peripheral arteries, intimal hyperplasia at the distal anastomosis is the major cause of prosthetic vascular graft failure. Pharmacologic efforts to minimize intimal hyperplasia in small vessel anastomoses have thus far been unsuccesful. This approach does not directly address the biomechanical factors which prevail at distal anastomoses to small vessels or the nature of the changes in the flow field at anastomotic sites. Hemodynamic factors associated with branch geometry and with the mechanical properties of the artery wall correlate closely with the localization of intimal thickening and atherosclerosis. Vascular anastomoses affect near-wall flow properties by altering geometry, wall compliance and motion, and flow velocities about the anastomotic junction. It is our working hypothesis that the distribution of anastomotic intimal thickening or hyperplasia corresponds to the distribution of shear stress acting on the wall at the fluid-wall interface and occurs principally in regions of lowered and oscillartory shear stress, i.e., where local particle residence time is increased. We therefore propose to construct vascular bypass grafts in dogs under conditions of differing anastomotic geometry, flow conditions an wall characteristics such as those which occur in patients undergoing lower extremity arterial bypass surgery and to assess the effects of the associated mechanical and configurational factors on the localization and degree of anastomotic intimal thickening during the course of the healing process. To accomplish this we will quantify the spatial distribution of anastomotic intimal thickening using computer- assisted three dimensional reconstruction techniques and correlate these findings with the spatial distribution in scale models of wall shear stress and particle residence time in relation to geometry, to graft versus artery compliance and to the distribution of flow velocities in the perianastomatic vessels. The findings would be expected to define clearly and quantitatively, for the first time, the actual localization of perianastomotic intimal thickening and the corresponding flow field conditions, and to identify the optimal biomechanical conditions for minimizing anastomotic intimal hyperplasia.

Our long term objective is to quantitively define the varying hemodynamic forces which act on the human thoracoabdominal aorta resulting in biomechanical stresses and strains in the vessel wall which may over time result in mechanical failure of the aortic wall and aneurysmal enlargement. Since the infrarenal abdominal aorta is particularly prone to aneurysm formation and the thoracic aorta is resistant, we will compare the two segments of aorta to determine predisposing factors for aneurysm formation. Our hypothesis is that hemodynamic forces and cumulative biomechanical stresses and strains, along with genetic susceptibility and superimposed atherogenic and humoral factors combine to result in aortic wall tissue failure and aneurysm formation. These factors, coincide, and are magnified in the abdominal aorta making it more prone to AAA. We will characterize and contrast the structural, compositional and biomechanical properties of the abdominal and thoracic aorta in humans and determine age related changes of the aortic wall. Utilizing MR imaging techniques, we will noninvasively assess thoracic and abdominal aortic blood flow in young (20-35 year old) and old (60-75 year old) normal adults as well as in patients with AAA. We will determine the 3 dimensional pulstaile flow field and quantitate differences in aortic wall strain between the abdominal and thoracic aorta. Physical models and in vivo animal experiments will be used to validate MR measurements and to develop and validate computational methods to model and predict biomechanical stress and strain of the aortic wall. These data will be used to construct a computational model of the human thoracoabdominal aorta which characterizes the 3 D pulsatile flow environment under a wide variation of conditions, such as changes in exercise states, cardiac output and blood pressure and quantify the real time aortic wall stress and strain pattern. Similarly, we will construct a computational biomechanical model of a human abdominal aortic aneurysm which will enable calculation of cumulative aortic wall stress loads over time. This will be used for predictive modeling of tissue failure and aneurysm enlargement and will be useful to evaluate strategies for therapies aimed at altering aortic wall tissue characteristics and matrix structure as well as in evaluating treatment strategies such as aortic stent grafts and open repair of the abdominal aortic aneurysms.

ITR/AP: Simulation-Based Medical Planning for Cardiovascular Disease

The current paradigm for interventional and surgery planning for the treatment of congenital and acquired cardiovascular disease relies exclusively on diagnostic imaging data to define the present state of the patient, empirical data to evaluate the efficacy of prior treatments for similar patients, and the judgement of the surgeon to decide on a preferred treatment. The individual variability and inherent complexity of human biological systems is such that diagnostic imaging and empirical data alone are insufficient to predict the outcome of a given treatment for an individual patient.

The specific objectives described in the present proposal are to develop a Problem Solving Environment for Simulation-Based Medical Planning combining (i) the construction of patient-specific preoperative geometric models of the human vascular system directly from medical imaging data, (ii) the modification of these models to incorporate multiple potential interventional and surgical plans, (iii) the generation of finite element meshes of the treatment plans, (iv) the simulation of blood flow in these patient-specific models, and (v) the visualization and quantification of resulting physiologic information. Techniques for identifying vessel boundaries from computed tomography (CT) and magnetic resonance imaging (MRI) data using two- and three-dimensional level set methods will be improved to enhance accuracy and efficiency.
The ultimate result of the successful completion of the outlined tasks will be the development of an integrated Problem Solving Environment for Simulation-Based Medical Planning incorporating image segmentation, geometric modeling, mesh generation, computational mechanics, and scientific visualization techniques.

DESCRIPTION (provided by applicant): The human aorta is susceptible to both atherosclerotic plaque deposition and aneurysmal enlargement. While the specific causal mechanisms are unclear, biomechanical factors are thought to play an important role, particularly in the differing susceptibility of the thoracic and abdominal aorta to these degenerative changes. We developed a non-invasive magnetic resonance method to quantify aortic wall biomechanics in vivo and found that aortic wall motion and strain vary around the aortic circumference with significant local variation in aortic structure. This is consistent with clinical observations of eccentric plaque localization and focal aneurysm formation. Furthermore, aortic biomechanics are impacted by implanted endovascular devices such as stents and stent grafts which are used to treat occlusive disease and aneurysms of the aorta with unknown long term consequences. During this grant, we will relate varying aortic strain patterns measured in vivo to the 3-dimensional microarchitecture of normal porcine aortas. We will then implant endovascular aortic stents and stent grafts in experimental animals to modify aortic wall biomechanics. We will assess the acute and chronic impact on in vivo aortic wall biomechanics and long-term changes in aortic microstructure. We will utilize the same in vivo magnetic resonance imaging technique to assess aortic wall motion and cyclic strain in humans and quantitate the differences about the circumference and along the length of the aorta. We will study both young and elderly healthy volunteers in order to discern age and gender related differences in aortic wall biomechanics. These data will provide valuable insights into our understanding of the structure and compostition of the aorta in relation to biomechanical strain and will provide a means of assessing the impact on the aortic wall of interventional treatments using implanted aortic devices. Further, these studies will provide a framework to understand normal age-related and degenerative changes affecting the human aorta. Finally, it will provide a quantitative basis for application of aortic magnetic resonance imaging in larger human clinical trials involving patients with aneurysmal or occlusive disease of the aorta, both before and after endovascular treatment.

PI name: B.L. Pruitt
Institution: Stanford University
Proposal Number: 0735551

EFRI-CBE: Engineering of Cardiovascular Cellular Interfaces and Tissue Constructs


Abstract


Cardiac cells and tissue are ideal targets for regenerative medicine and fundamental studies of the interplay of cellular and biomolecular level signaling and response for several reasons. First, observation of successful stem cell differentiation to cardiac myocytes is facilitated by readily identifiable immunohistochemical markers as well as characteristic electrical action potentials and mechanical contractions. Second, explanted cells in culture lose their morphology and organization in the absence of drugs or electromechanical stimulation, suggesting that cellular organization is dependent on these cues. Last, myocardium damaged during a heart attack does not regenerate and the weakened muscle results in heart failure. Fundamental understanding of how cardiac myocytes and heart tissue can be regenerated is essential to creating successful therapies for patients with heart disease (affecting 71 million Americans). Recently, several studies have shown that stem cells may offer regenerative potential through direct injection of cells into the damaged myocardium or in situ repair using engineered tissue grafts.

The Intellectual Merit of this project lies in the development of basic knowledge and models for cell response to environmental cues. Pluripotent cell responses to changes in environment offer a testbed for characterizing the thresholds and mechanisms of environmental adaptation and remodeling. The outcomes of the baseline and coupled experiments will be made available as a database for other researchers. Models and results will be disseminated by publication and seminars for researchers in the field as well as public seminar forums.

The Broader Impacts of this work lie in the enhanced knowledge of cell signaling and differentiation, the role of culture environmental parameters in tissue engineering, and the enhanced design guidance and technology developed which will ultimately enable regenerative therapies for victims of heart disease. Topics of this research will be incorporated in modules for teaching basic engineering and materials courses and the Principal Investigators (PIs) will recruit undergraduates for research experiences in their labs. The PIs actively participate in outreach, undergraduate research opportunities, and research experience for teacher programs and will expand these efforts related to this project. A workshop on the research topics will be held in the final year of the project.

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (05) Comparative Effectiveness Research (CER) and specific Challenge Topic 05-EB-105: Comparative Effectiveness of Medical Implants. The prevalence of abdominal aortic aneurysms (AAA) has increased significantly in the American population, affecting 5-7% of Americans over age 60. During the past decade endovascular aneurysm repair has become the primary treatment for aneurysm disease. Currently, there are 5 FDA approved abdominal aortic aneurysm endografts: Medtronic AneuRx, Gore Excluder, Cook Zenith, Endologix Powerlink, and Medtronic Talent. Each of these devices presents different designs and fixation mechanisms. Endovascular repair is a minimally invasively procedure that reduces perioperative morbidity and mortality when compared to open repairs. However, endovascular procedures are prone to late failure due to the loss of long-term positional stability (i.e., migration) of the endograft as a result of the pulsatile forces of blood flow. Endograft failure results in costly secondary procedures, conversion to open repair, long-term surveillance, and death. Understanding the biomechanical environment experienced by endografts in vivo is a critical factor to ensure correct functioning and long term durability of the device. The goal of this work is two-fold: First, we will develop and apply a set of tools to characterize the mechanical behavior of endografts in vivo with the overall goal of determining the likelihood of migration of the endograft. Second, we will perform a comparative effectiveness study with regards to migration of the 5 AAA endografts. We will use 3D segmentation techniques to generate patient- specific computer models of AAAs with implanted endografts. Then, we will perform Computational Fluid Dynamics (CFD) analyses to evaluate the hemodynamic forces acting on the device. The CFD analysis will rely on sophisticated methods for boundary condition specification to obtain realistic distributions of flow and pressure in the computer model of the endograft. We will then perform a Computational Solid Mechanics (CSM) analysis to evaluate the fixation forces developed by the endograft in the attachment zones with the vessel wall. Longitudinal studies of serial follow-up imaging of patients treated with each endograft will provide the necessary statistical data to obtain a likelihood of migration for the computational studies. The research team we have assembled consists of leading bioengineers, mechanical engineers, radiologists, and clinicians and will be led by Dr Christopher K. Zarins at Stanford, a leading researcher in the development and clinical application of endovascular treatments for AAA disease. Dr. Zarins has been a strong advocate for using imaging and simulation tools to improve medical device design and develop safer and more effective medical products. This research will be the first attempt to characterize the problem of migration of AAA endografts using a combination of best-in-class imaging, CFD and Computational Solid Mechanics tools. Furthermore, this work will provide the first comparative effectiveness study of the 5 current FDA approved AAA endografts. Resistance to aortic endograft migration: comparative effectiveness of FDA approved devices. Public Health Relevance: Endovascular repair has become the primary treatment for abdominal aortic aneurysm (AAA) disease. There are currently 5 FDA approved endograft devices for AAA repair. The true in-vivo biomechanical environment experienced by these devices is poorly understood. Furthermore, there are currently no studies that compare the performance of the different devices with regards to their long term positional stability (migration).